Mucous membranes of the entire digestive tract, including the oral cavity, are composed of epithelial cells which have a short life span. This life span varies with the location along the tract but it is estimated that the average cell along the tract has a life of about 2 to 3 days. There is in the tract a constant replenishment by cell division, which has the effect of renewing the lining of the digestive tract constantly so that injuries have only a temporary effect and any damage resulting from contact with possibly injurious substances ingested with food are quickly repaired. This rapid renewal process also, however, renders the tissue more susceptible to certain agents which impair cell division, for example, anti-cancer drugs. (Harrison's Principles of Internal Medicine, 12th ed., Ch. 41, 1991, McGraw-Hill).
Periodontal diseases and diseases of oral mucosa usually involve microorganisms, but a number of factors influence the integrity of the tissue itself. For example, it has been shown that about 10% of persons with Inflammatory Bowel Disease have Aphthous ulcers of the mouth (Harrison's Principles, cited, Idiopathic Inflammatory Bowel Disease, Thomson A. B. R. ed., M. O. M. Printers, Ottawa, 1982, Ch. 23). Inflammatory Bowel Disease has been associated with defects in the protective lining of the gastrointestinal tract (Burton A. F., Anderson, F. H., American Journal of Gastroenterology 1983, 78: 19-22; Olafson et al., Scandinavian Journal of Gastroenterology 1990, 25: 321-328; Hollander et al., Annals of Internal Medicine 1986, 05: 883-885).
The mucosa of the mouth has a high rate of cell turnover as does the rest of the digestive tract and what applies to tissue elsewhere in the tract has equal significance in the oral cavity. Proglumide, a drug which protects against an ulcer in the stomach, has been reported to increase the synthesis of glycoproteins and glycosaminoglycans, which are considered to provide protection by maintaining the integrity of the lining of the stomach (Umetsu T. et al., European Journal of Pharmacology 1980, 69: 69-77).
Several patents disclose amino sugars for treatment of disorders.
U.S. Pat. No. 4,590,067, May 20, 1986, Meisner, Peritain Ltd., discloses a composition for preventing and treating periodontal disease comprising bone meal, ascorbic acid, tyrosine and either glucosamine or cysteine. N-acetyl glucosamine is not disclosed.
French Patent No. 2,473,887, Jul. 24, 1981, discloses the use of biochemical precursors of glucosamineglycans for the treatment of vascular disorders of functional or organic origin in which there is insufficient blood flow to the limbs, for asphyxic hypoxydotic symptoms, and in cosmetology, for skin defects caused by insufficient circulation to the skin. The precursors, which include N-acetylglucosamine, increase the elasticity of perivascular tissue, resulting in an increase in arterio-capillary blood flow, without having a vasodilating action.
U.S. Pat. No. 4,006,224, Feb. 1, 1977, J. F. Prudden, discloses the treatment of ulcerative colitis or regional enteritis in a mammal by administering D-glucosamine, or one of its salts. Equal or superior results to the conventional treatments of the two conditions are obtained. The dose is 20-300 mg/kg of D-glucosamine, HCl daily. In a clinical trial, a patient with Crohn's Disease that was not affected by ACTH or prednisone was given D-glucosamine, HCl subcutaneously. The symptoms stopped after several weeks of treatment.
WO A 8 702 244, N. Hendry, EP A 0178602, Peritain Ltd. and French Patent A 2016 182, Rotta Research Labratorium SpA, are of interest to this subject.
Hendry discloses a preparation for tissue growth regulation comprising (a) at least one of N-acetyl-D-glucosamine or an oligomer thereof, or a deacylated derivative thereof, or a substituted product of these compounds; (b) at least one of biotin or an analog or derivative biotin, or biologically active residue thereof; and (c) a divalent metal cation together with a pharmaceutically acceptable anion.
Both Meisner and Hendry refer to amino sugars, including glucosamine and N-acetyl glucosamine. Their use is as one of a mixture of several other known nutrients, which have various effects on cell growth.
A key difference in the applicant's proposed use of NAG is this: It is proposed as a source of amino sugar for the synthesis of molecules such as glycoproteins and glycosaminoglycans, which are rich in NAG and the synthesis of which is stimulated by NAG.
NAG is formed from glucosamine and NAG is then directly converted into other amino sugars. NAG is thus a key substance, and in the applicant's work with intestinal tissue, it was found that the formation of NAG itself from glucosamine was the slow part of the process. This necessitates the use of NAG, specifically, and not a deacetylated form, or oligomer.
NAG, moreover, is more stable than glucosamine, is a neutral substance and is readily assimilated by tissues and utilized, whereas most oligomers are not.
The proposed use of NAG is unique and differs from existing art.
An article entitled "Decreased Incorporation of .sup.14 C-Glucosamine Relative to .sup.3 H-N-Acetyl Glucosamine in the Intestinal Mucosa of Patients with Inflammatory Bowel Disease", A. F. Burton and F. H. Anderson, vol. 78, No. 1, 1983, American Journal of Gastroenterology, discloses evidence that the synthesis of glycoproteins in intestinal mucosa of patients afflicted with inflammatory bowel disease is deficient in the diseased tissues of such patients. The article discusses possible reasons for the deficiency. However, no suggestions for alleviating the deficiency are made.